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Mura et al. The peritoneal metastases from GC

INTRODUCTION Peritoneal dissemination of free cancer cells happens
through exfoliation from the tumor and leads to direct
The regional metastatic spread of gastric cancer invasion of the mesothelium. Surgery itself may
(GC) usually results in peritoneal carcinomatosis produce intra-operative dissemination of cancer cells
(PC). When GC patients are explored for potentially by severed lymphatics, intraperitoneal blood loss,
curative resection, 10-20% of them are found to have trauma at narrow margins of resection etc.. According
peritoneal metastases. Furthermore, in case of to the “tumor cell entrapment hypothesis” proposed
[1]
cancer infiltration of the serosal layer of the stomach, by Sugarbaker PH, immediately after a surgical
PC is present at first diagnosis of the cancer in 15-50% procedure the endoperitoneal free cancer cells
of cases and peritoneal recurrence develops in 35-60% which are spontaneously exfoliated or iatrogenically
of such patients after radical resection. PC is the only disseminated adhere to the damaged surface created
site of metastasis in 40-60% of patients. [2,3] Therefore, by surgery; they are trapped by fibrin and stimulated by
peritoneal metastases alone usually result in death for growth factors of the wound healing and inflammation
20-40% of patients with GC. [4] processes, with tumor cell implant on the visceral and
parietal peritoneum. The nodule of carcinomatosis in
Conventional surgery is not adequate for PC; current this way becomes a hypoxic, and relatively immune to
treatments are systemic chemotherapy and palliative systemic chemotherapy, environment. [15]
therapy, with no hope of cure. In selected cases
and in experienced centers, the association of more Tumor cells can also diffuse through the “milky-spots”,
aggressive surgery with multimodal loco-regional little cribriform “stomata” present on the peritoneal
treatments has shown to achieve prolonged survival surface, communicating between peritoneal cavity and
and reduced peritoneal recurrences. [5-7] lymphatic vessels, with the function of re-absorption
of abdominal fluids. Milky spots are mainly composed
PHYSIO-PATHOLOGICAL FEATURES OF PC of macrophages and B1 cells; there are compelling
data to consider the milky spots as unique secondary
The molecular mechanisms by which GC undergoes lymphoid organs. The peritoneal free cancer cells
[16]
PC are not completely clear. Chemokines (CXC) are are trapped during their passage through the spots
surely involved. They are small secretory proteins and attacked by inflammatory and immuno-response
controlling migration and activation of leukocytes and cells, forming a hypoxic nodule. The milky spots
[17]
other types of cell through interactions with a group of are mainly localized in the omentum and in the sub-
seven trans-membrane G protein-coupled receptors. diaphragmatic areas, which are in fact the preferential
CXC may also promote growth/survival and metastasis sites of distribution of peritoneal metastases. [18]
of several malignancies. [8-11] There is evidence that
the axis between CXCL12 (highly expressed in THE TREATMENT OF PC
peritoneum than in the liver or lymphnodes) and the
receptor CXCR4 plays a role in the development of The PC arising from GC has ever been considered as
PC from GC. [12,13] The CXCR4 antagonist AMD3100 a final stage of the disease, with no chances of cure
prevents experimental PC by NUGC4 cells in nude but palliation. The prognosis of PC for GC is very poor,
mice. In human, the CXCR4 expression in primary worse than that of other metastatic sites, [19,20] with a
tumors of patients with advanced GC significantly median survival after diagnosis of only 3-7 months and
correlates with the occurrence of PC. Furthermore, 5-year survival of 0%. [1,3] The traditional approach by
CXCR4-expressing GC cells are preferentially surgeons is just palliation, whenever possible.
attracted to the peritoneum cavity where its ligand
CXCL12 is abundantly produced. The CXCL12/ Systemic chemotherapy
CXCR4 axis is influenced by interaction with the In last 15 years systemic chemotherapy (adjuvant or
vascular endothelial growth factor (VEGF). VEGF is neoadjuvant) [21-26] and adjuvant chemo-radiation [27,28]
[14]
markedly elevated in malignant ascites and is one of do not have significantly lowered the rate of distant

the essential elements in the development of PC. metastases, including peritoneal recurrence. In
[12]
Such results suggest that the expression of CXCR4 metastatic GC, systemic chemotherapy improves
in biopsy specimen from primary gastric tumors may median survival to only 8-14 months, [29-31] without
be useful for preoperative evaluation of risks for the great improving by adding targeted therapy. [32,33] GC
occurrence of PC. Evaluation of CXCL12 levels in patients with PC have a significantly reduced rate of
intraoperative washing of abdominal cavity in patients tumor response to chemotherapy with reported rates
with advanced GC has been proposed as a predictive of response of 14-25%. [34,35] The poor response of
molecular marker for the risk of PC. PC to systemic chemotherapy is due to the presence
366 Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ September 18, 2016